Structure and Function - Week 6 Neuropharmacology

Question 1

For a diagnosis of depression, what is the criteria for the symptoms? (2)

Answer 1

Over same two week period

DSM-5: Must have five or more symptoms, which must include one of the core symptoms

Question 2

What are the core symptoms of depression (2)

Answer 2

Low mood
Anhedonia (loss of interest or pleasure)

Question 3

What are the other symptoms of depression (6)

Answer 3

Changes in weight or appetite
Fatigue or loss of energy
Sleep changes (insomnia or hypersomnia)
Reduced ability to think or concentrate
Psychomotor (restless or slow movement)
Feelings of worthlessness or guilt
Thoughts of death, self-harm, or suicide attempt.

Question 4

Describe diagnosis of depression (3)

Answer 4

Typically seen in primary care – most cases are mild or moderate. Complex or severe cases may be referred to specialist care.

May order tests to rule out hypothyroidism, deficiencies, chronic disease etc. but not routinely done

Often co-occurs with anxiety, as well as with chronic disease, pain etc

Question 5

Describe the onset of depression (3)

Answer 5

Check notes

Question 6

Describe epidemiology of depression (3)

Answer 6

Depression is more common in women than men (unknown why) but rates of death by suicide are much higher in men

Higher rates of depression in those living in deprived areas, living with a disability, and unemployed (unknown cause and effect)

Question 7

What is disability adjusted life years? (1)

Answer 7

Takes into account quality of life and risk of premature death from a medical condition

Question 8

What are the different treatments for depression? (6)

Answer 8

Medication (may be needed short or long term)
Therapy or Counselling (including CBT)
Life changes (work, home life, diet, exercise etc.)
Creative therapies (see Bryan Charnley’s work)
Electroconvulsive therapy (e.g. for major depression)
Magnetic stimulation

Question 9

What is anxiety? (2)

Answer 9

Anxiety is a biological process – evolutionary benefit to anticipating threats

Described as feelings of worry, dread, unease in absence of a current threat or danger (difference with “fear”).

Question 10

Describe the symptoms of anxiety (3)

Answer 10

Vary depending on the specific type e.g. the anxiety may be associated with social situations (social anxiety disorder).

Psychological: irritability, restlessness, panic, anxious anticipation, worry, dread, difficulty concentrating.

Somatic: Palpitations, tachycardia, hyperventilation, dry mouth, nausea, stomach pains, urinary frequency, dizziness, muscle tension, sweating, tremor, pain in chest, and more.

Question 11

What is generalised anxiety disorder? (3)

Answer 11

Excessive anxiety and worry, occurring more days than not for at least 6 months, about a number of events or activities (such as work or school performance). The person finds it difficult to control the worry

The anxiety and worry are associated with three or more of certain symptoms

Ruled out not due to effects of a substance, another medical condition, or another mental disorder (e.g. posttraumatic stress disorder).

Question 12

What are the symptoms required for generalised anxiety disorder? (6)

Answer 12

Restlessness/feeling on edge
Difficulty concentrating or mind going blank
Irritability
Being easily fatigued
Muscle tension
Sleep disturbance (difficulty falling or staying asleep, or restless unsatisfying sleep)

Question 13

Describe the onset of anxiety disorders (2)

Answer 13

Average age of onset tends to be younger than for mood disorders but it also depends on the type of anxiety disorder (huge variability)

Question 14

Describe the epidemiology of anxiety (3)

Answer 14

Like depression, anxiety is also more common in women but unknown why (difference more pronounced in young).

Many estimates place anxiety disorders 2nd in terms of impact on disability adjusted life years (DALYs).

Question 15

Describe the treatments available for anxiety disorders (4)

Answer 15

Medication (may be needed short or long term) (antidepressant can be given - anxiolytic)
Therapy or Counselling (including CBT)
Life changes (work, home life, diet, exercise etc.)
Creative therapies

Question 16

How is activity of monoamine oxidase inhibited? (1)

Answer 16

Anti-TB agents

Question 17

What is MAO? (2)

Answer 17

Monoamine oxidase (MAO) – an enzyme attached to the outer membrane of mitochondria.

Two subtypes – A and B

Breaks down monoamines

Question 18

Describe how monoamines are broken down by MAO (2)

Answer 18

Break down of monoamines to metabolites by MAO

Reduced availability of monoamines and releasable pool

Question 19

Which monoamine does MAO-A break down? (1)

Answer 19

5-HT and norepinephrine mostly broken down by MAO-A

Question 20

Which monoamine does MAO-B break down? (1)

Answer 20

Dopamine broken down by MAO-A and -B

Question 21

What happens when MAO is inhibited? (5)

Answer 21

Anti-TB agents targeted both MAO-A and MAO-B
Enzyme inhibited
Monoamines not broken down
Monoamine availability through releasable pool increases
Leads to monoamine hypothesis

Question 22

Describe monoamine hypothesis (1)

Answer 22

Increased monoamine activity

Question 23

Describe why Non-selective MAOIs not used as first line treatment for depression? (5)

Answer 23

Elevate levels of norepinephrine when MAO-A and MAO-B inhibited
This can bind to alpha1 adrenergic receptor
Cause blood vessel constriction
Blood pressure rises
Can remain within manageable levels
Patient can experience hyper-tensive crisis - can lead to death

Question 24

Describe the cheese reaction (7)

Answer 24

Foods contain tyramine - normally broken down by MOA in gut
Not broken down due to inhibition of MAOA
Enters blood stream
Not broken down MAO in neurons
Displaces noradrenaline from its vesicles
Noradrenaline enters blood stream
Raise blood pressure to dangerous levels and can cause death

Question 25

What are the adverse effects of MAOIs? (4)

Answer 25

Common adverse effects include insomnia, tremors, dry mouth, excitement.

Some may cause hepatotoxicity, and some are very toxic in overdose compared to newer antidepressants.

Question 26

Describe the use of MAOIs (2)

Answer 26

Range of clinical uses to treat depression and other disorders. Due to adverse effects, non-selective MAOIs would not typically be a first line treatment choice

Question 27

What are tricyclic antidepressants (TCAs)? (2)

Answer 27

Target monoamines and avoid non-selective MAOI adverse effects

Question 28

Describe the mechanism of action of TCAs (4)

Answer 28

TCA blockade of 5-HT and norepinephrine transporters

Prevents reuptake.

Increases levels in the synaptic cleft.

Most have weak efficacy for dopamine transporters.

Question 29

Describe adverse effects of TCAs (4)

Answer 29

Sedation, weight gain, confusion, motor incoordination – mostly pass after a few weeks.

Off-target anti-cholinergic side effects such as dry mouth, blurred vision, constipation etc

Cardiotoxicity, particularly in overdose, due to off-target effects on sodium and calcium channels

Question 30

Describe interaction of TCAs with other drugs (1)

Answer 30

Interaction with antihypertensive drugs and alcohol (can cause respiratory distress)

Question 31

Describe rational drug design of SSRIs (3)

Answer 31

Selective to 5-HT reuptake through serotonin transporters (SERT)

Though some efficacy to norepinephrine and/or dopamine transporters

Question 32

Describe mechanism of action of SSRIs (2)

Answer 32

SSRIs bind to transporter
Prevent serotonin from re-entering pre-synaptic terminal

Question 33

How do SSRIs compare to MAOIs? (1)

Answer 33

SSRIs do not cause a tyramine “cheese reaction”

Question 34

How do SSRIs compare to TCAs? (2)

Answer 34

SSRIs have minimal anticholinergic effects

SSRIs have less of a sedative effect

Question 35

Advantages of SSRIs (2)

Answer 35

Less dangerous in overdose – both TCAs and MAOIs are more toxic.

Question 36

Describe the adverse effects of SSRIs (4)

Answer 36

Some of the common adverse effects: Nausea, insomnia, agitation, and loss of libido. May improve with time

Cardiotoxicity possible as with TCAs – less likely though

Serotonin syndrome on overdose as in MAOIs and TCAs. Note at therapeutic doses can mix SSRIs with TCAs but not with MAOIs.

Under 18s – specific adverse effects such as aggression or suicidality. Elderly – may cause low sodium levels.

Question 37

Describe the use of SSRIs (2)

Answer 37

Wide range of uses in mental disorders. Typically the first line of treatment for MDD unless contraindicated or another condition present e.g. depression plus chronic pain benefits from TCAs

Question 38

What is the advantage of benzodiazepines? (2)

Answer 38

Broader therapeutic window than barbiturates – rarely a cause of death when taken alone (dangerous with alcohol, opioids, etc.)

Question 39

Describe mechanism of action of benzodiazepines (4)

Answer 39

Positive allosteric modulators (PAMs) of GABAA receptors:
Increase the affinity of GABA for the GABAA receptor – enhance frequency of Cl- channel opening

GABA A - ionotropic receptor
Binds and channel opens
Cl- enter and flow into cell
Hyperpolarises cell
Therefore, GABA has inhibitory effect

Question 40

Describe adverse effects of benzodiazepines (3)

Answer 40

Most common adverse effects: drowsiness, confusion, impaired coordination, anterograde amnesia

Abruptly stopping use can lead to rebound anxiety, tremor, dizziness, insomnia, etc. – patients advised to taper.

Withdrawal syndrome can occur following chronic use, even with tapering

Question 41

Describe propranolol? (3)

Answer 41

Beta blocker

Can help control somatic symptoms of anxiety (heart palpitations, tachycardia, sweating, trembling, etc.)

Sometimes used to treat performance anxiety – onset of action ~60 mins.

Question 42

Describe the clinical use of propranolol (2)

Answer 42

Indicated for generalised anxiety disorder
Improvement will typically begin within 1 week.

Question 43

Describe mechanism of action of buspirons (3)

Answer 43

5-HT1A receptor partial agonist

Gi coupled so reduces firing rate (also acts as an autoreceptor to reduce 5-HT release)

Also an antagonist at D2-D4 and other 5-HT receptors but with lower affinity – possibly complex mechanism of action

Question 44

Describe clinical use of buspirone (3)

Answer 44

Indicated for short-term treatment of anxiety, despite there delayed therapeutic effect (~2 weeks).

Efficacy appears highest for generalised anxiety disorder.

Question 45

Describe pregabalin (3)

Answer 45

Analogue of GABA but does not bind directly to GABA receptors - binds instead to the α2δ subunit of voltage-gated calcium channels (VGCCs).

Blocking VGCCs associated with decreased excitatory neurotransmitter release

Question 46

Describe the clinical use of pregabalin (2)

Answer 46

Indicated for generalised anxiety disorder
Improvement will typically begin within 1 week